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CASE REPORTS
Herpes Simplex Encephalitis in an Anergic Patient
RICHARD PRICE, M.D.
NORMAN L. CHERNIK, M.D.
New York, New York
LUIZ HORTA-BARBOSA, D.V.M
Bethesda, Maryland
JEROME B. POSNER, M.D
New York, New York
From the Neuropsychiatric Service, Memori- al Hospital for Cancer and Allied Diseases, New York, New York; and the Section on In- fectious Disease, Perinatal Research Branch, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland 20014. Requests for reprints should be ad- dressed to Dr. Jerome B. Posner, Neuropsy- chiatric Service, Memorial Sloan-Kettering Cancer Center, 444 East 68th Street, New York, New York 10021. Manuscript received September 1, 1972; revision accepted Sep- tember 26, 1972.
A patient with Hodgkin’s disease and impaired immunity in whom encephalitis developed due to herpesvirus hominis type 1 is described. The patient’s clinical course was atypical, being slowly progressive over seven weeks beginning with right fron- toparietal dysfunction but progressively involving both hemi- spheres and the brainstem. The pathologic features were simi- larly unusual, consisting of widespread neuronal destruction, astiocytic proliferation and Cowdry type A inclusion bodies. Ab- sent were the typical inflammatory changes and characteristic hemorrhagic necrosis of the medial temporal and inferior frontal lobes. lntraventricular administration of cytosine arabinoside failed to alter his course. The patient’s depressed immune sys- tem appears to have been responsible for the atypical nature of his illness. The variance of the illness suggests that in the more usual case of herpes simplex encephalitis both direct cytotoxic- ity of the virus and host immune responses contribute to the pathogenesis of the disease.
Herpes simplex encephalitis is the most common sporadic viral
encephalitis [l]. It is usually a fulminant and necrotizing dis-
ease (2-4). Herpes simplex has not previously been reported
to cause encephalitis in a patient whose immunologic mecha-
nisms are compromised. We describe such a patient in whom
both the clinical and pathologic features of the encephalitis were atypical, the illness being neither acute nor necrotizing.
This case suggests that both direct effects of the virus and host
immune responses contribute to the pathogenesis of the usual
case of herpes simplex encephalitis.
CASE REPORT
A 40 year old man was admitted to Memorial Hospital on September 2, 1971 following a generalized seizure. In February 1970 he had an enlarged right supraclavicular lymph node. Biopsy revealed Hodg- kin’s disease, mixed ceil pattern, and he was referred to Memorial Hospital where widespread lymph node involvement was detected. He received radiation therapy to the “total node bearing area” from August 6 through November 17, 1970. In April 1971 herpes zoster in- fection appeared over dermatomes of the left fifth and sixth cervical segments. In July 1971 he had spiking temperatures to 104°F and was treated with vinblastine (Velban@), receiving a total dose of 33 mg intravenously between July 26 and August 30 via weekly or fort- nightly injection. On August 23, the administration of prednisone, 40
222 February 1973 The American Journal of Medicine Volume 54
HERPES SIMPLEX ENCEPHALITIS-PRICE ET AL.
Brain Biopsy
Clinical course
mo WBCcount 4t~r)~r
0
ml-
Temperature 1~ _
%L
Prednisone 100 1
Figure 1. The clinical course and equiv0alent 0
treatment of the patient during the ,,,,,,,,,,,,,,,~,II,,~~,~,,1111,,~,1,
2 10 Xl 30 2 8 period of hospitalization. Sept. Oct.
mg/day, was begun; after one week the dose was de-
creased to 20 mg/day. His fever subsided.
Neurologic symptoms began in mid-August 1971
when clumsiness of the left hand developed followed
by numbness starting in the thumb and index finger
and gradually spreading to involve all the fingers of the
left hand. Later there was intermittent numbness of his
left upper lip and occasionally decreased vision in the
left field of vision. On the morning of admission he ex-
perienced “twitching” of his left hand followed by a
generalized seizure. His past medical history included
chicken pox and a tonsillectomy in childhood.
On examination the vital signs were normal and the
patient appeared in good health. The general physical
examination was normal except for depigmented scars
over the left fifth and sixth cervical dermatomes
(herpes zoster infection). His intellect was normal. He
intermittently extinguished the left inferior visual quad-
rant on double simultaneous stimulation. The left cor-
neal reflex was slightly depressed, and there was
mildly decreased touch and position sense over the
left side of his face as well as facial weakness over
the lower left side. On sensory examination there was
decreased sensation to all modalities over the left fifth
and sixth cervical “postherpetic” scar region. In addi-
tion, over the remainder of the arm (and particularly
the hand), a decrease in position sense, two-point dis-
crimination and stereognosis was noted. Pain, touch
and temperature sensation were relatively preserved.
Abnormalities of the motor examination were confined
to the left arm. Almost continuous clonic activity was
present at a rate of approximately 1 /second. This con-
sisted of flexion of the fingers and thumb and, at
times, the wrist as well. There was diminished motor
power in all muscle groups of the arm except the tri-
ceps muscle. Atrophy of the left deltoid, biceps bra-
chii, supraspinatus and infraspinatus muscles was
again evident. The left arm was also quite clumsy, but
coordination was normal in all movements in the other
three extremities. Gait and station were normal. The
deep tendon reflexes were active and symmetrical ex-
cept for loss of biceps and brachioradialis muscles on
the left and bilaterally diminished ankle jerks. Plantar
responses were flexor.
The initial white blood cell count was 5,800 cells/
mm3. However, a steady decline in this count oc-
curred such that prior to his death it had fallen to 500
cells/mm3 (Figure 1). The platelet count exhibited a
similar decline, being 200,000/mm3 on admission and
3,000/mm3 prior to death. Liver function tests were
initially mildly abnormal and demonstrated increasing
dysfunction. The serologic test for syphilis (VDRL).
antinuclear antibody and Sabin-Feldman dye tests for
toxoplasmosis were negative.
The first lumbar puncture revealed normal pressure,
50 red blood cells and 1 mononuclear cell/mm,3 pro-
tein 59 mg/lOO ml and sugar 59 mg/lOO ml. Cytolog-
ic examination was negative. The first ventricular
specimen following placement of an Ommaya reser-
voir [5] contained 41,211 red blood cells, 255 poly-
morphonuclear cells and 45 mononuclear cells/mm.3
Subsequent specimens showed clearing of cells and
protein concentrations from 14 to 26 mg/lOO ml. The
final specimen was acellular. Brain scan, right carotid
arteriogram and pneumoencephalogram were normal.
Electroencephalograms taken on September 3. Sep-
tember 10 and September 24 showed progressive
multifocal slow and sharp wave abnormalities which
correlated well with the patient’s clinical course.
Aspects of the patient’s course are depicted in Fig-
February 1973 The American Journal of Medicine Volume 54 223
HERPES SlMPLEX ENCEPHALITIS-PRICE ET AL.
Figure 2. Corona/ section of the brain. The appear-
ance is normal except for thinning and loss of defini- tion of the cortical gray over the convexity of the right
frontoparietal area (right arrow). The darker region in
the left hemisphere (left arrow) is an artifact. Conspic- uously absent in this and in all sections is the typical hemorrhagic necrosis of the temporal lobe.
Figure 3. Low power photomicrograph of the cere- bra/ cortex. There is disorganization of architecture,
neuronal loss and astrocytosis unaccompanied by meningeal or perivascular inflammation. Hematoxylin and eosin stain, original magnification X 20.
ure 1. Diphenylhydantoin (Dilantin@), diazepam (Val-
ium@) and phenobarbital controlled seizures only
transiently. His left-sided symptoms progressed to a
hemiparesis and hemisensory deficit on the left side.
On September. 6 the patient observed that his right
hand “did not feel right,” and on examination there
was defective graphesthesia and two-point discrimina-
tion on that side. Three days later a right Babinski re-
sponse was elicited. On September 13 his temperature
rose to 102°F. On September 14 biopsy of the right
parietal lobe of the brain was carried out under local
anesthesia; the following day the patient complained
of a marked increase in numbness and clumsiness of
his right hand, and he became unable to write or to
feed himself. On September 16 a second brain biopsy
was performed, this time of the right frontal lobe; cul-
tures were taken for virus. Also at that time, an Ommaya
reservoir was placed with a catheter in the right lateral
ventricle. Subsequently the patient was given cytosine
arabinoside (1 -P-d-arabinofuranosylcytosine) via the
reservoir (Figure 1). A total dose of 450 mg was admin-
istered intraventricularly over 10 days. Prednisone in
fluctuating dosage, cyclophosphamide (Cytoxan@) and
Velban were administered (Figure 1). On September 23
the patient complained of diplopia from a left lateral
rectus paresis. Also present at that time were a left
homonymous hemianopsia and severe proprioceptive
loss with incoordination of all four extremities. His gait
was broad-based and unsteady. The following day,
seizure activity increased bilaterally (yet independent-
ly), speech was slurred and the patient had great diffi-
culty in swallowing. On September 26 he was lethar-
gic, and on the following day urinary retention devel-
oped. Hiccoughing began and on September 28 be-
came severe. He became dysarthric and confused,
and by October 6 he was responsive only to noxious
stimuli. The following day, generalized seizures devel-
oped with bilateral synchronous tonic and clonic activ-
ity. He died on October 8, seven weeks after the onset
of neurologic symptoms.
PATHOLOGIC FINDINGS
At postmortem examination, the lungs were se-
verely affected by a hemorrhagic bronchopneu-
monia. The liver showed focal hemorrhagic necro-
sis and intranuclear inclusion bodies, suggesting
herpes virus infection. Focal infiltrates of Hodg-
kin’s disease were noted in the liver and spleen.
Bone marrow was markedly hypocellular with vir-
tual absence of hematopoietic elements. There was a moderate diffuse lymph node enlargement but lymphocytes were not present, the paren- chyma being replaced by sheets of tumor cells.
The brain weighed 1,500 g and was swollen. A ventricular catheter entered the dorsal surface of
the right mid-frontal lobe and a small biopsy site was present along the dorsal surface of the right occipital lobe. An area of hemorrhagic necrosis
surrounded the entrance of the ventricular cathe-
224 February 1973 The American Journal of Medicine Volume 54
HERPES SIMPLEX ENCEPHALITIS-PRICE ET AL.
Figure 4. A, high power photomi- crograph showing large in tranuclear inclusion bodies within astrocytes. Two of the affected cells are swollen. Note the characteristic halo sur- rounding the inclusion bodies formed by the peripheral margination of nu- clear chromatin. Hematoxylin and eosin stain, original magnification X 360. B, an adjacent field showing a markedly swollen neuron with an ec- centrically placed nucleus containing a large inclusion body.
ter. Otherwise, there were no areas of softening
or discoloration. The dura, leptomeninges and
vessels were unremarkable. Coronal sections of
the cerebral hemispheres at 0.5 cm intervals were
grossly normal except for the area of hemorrhagic necrosis which followed the pathway of the ven-
tricular catheter. In scattered areas, but most
notably in the right frontoparietal region, there
was a subtle loss of the normally sharp delinea-
tion of the cortical mantle (Figure 2). The brain- stem and cerebellum were unremarkable. Histo-
logic examination revealed scattered microscopic
foci of pallor of the neuropil in the cortex and cen-
tral gray with disorganization of the cortical archi-
tecture and varying degrees of neuronal degen-
eration and drop out (Figure 3). There was marked endothelial swelling and proliferation with
reactive astrocytosis and large numbers of eosin-
ophilic intranuclear inclusion bodies in neurons,
astrocytes, oligodendroglia and, occasionally, en-
dothelial cells (Figure 4). The lesions were scat-
tered throughout the hemispheres without predi-
lection for any particular area. The inclusion bod- ies were of large size and of the typical Cowdry
type A morphology [6]. Oligodendroglial nuclei
frequently appeared to be totally filled by more basophilic staining inclusion bodies and rare swol-
len neurons contained multiple small inclusions.
The notable features of the lesions were their limi-
tation to microscopic size fields, the blandness of the associated tissue changes resembling a low
grade ischemic process and the absence of
inflammatory cells. There was no necrosis of ves-
sel walls. Sections of the necrotic tissue sur- rounding the ventricular catheter showed a bland
necrosis with fresh hemorrhage and an absence of inflammation. The two biopsy specimens were carefully searched, but no inclusion bodies or
other pathologic changes were identified. Several immunologic and viral serologic studies
were carried out during the patient’s life and these
are summarized in Tables I and I I. All pointed to
impaired immunity except the high blood and
cerebrospinal fluid indirect hemagglutination titers
for herpesvirus hominis (HVH) type 1. In addi- tion, brain tissue obtained at the time of right
frontal lobe biopsy on September 17, 1971 was
cultured. Direct inoculation of biopsy material
(and later autopsy material) into human embryon- ic lung cells (Memorial Hospital) produced no
growth. Explant cultures were prepared with
Eagles minimal essential medium (EMEM) supple- mented with 20 per cent fetal bovine serum (Na-
tional Institutes of Health). Confluent monolayers of undifferentiated glial cells were obtained within
10 days. These cultures were maintained with
EMEM enriched with 2 per cent fetal bovine
serum and observed daily by phase microscopy.
After 10 to 14 days, a distinct cytopathic effect
represented by rounding and ballooning of a few
cells was noticed in the cell sheets. Indirect im- munofluorescent assays performed from the cul-
TABLE I Immunologic Studies
Clinical Test Normal Patient
“Humoral” Immunity
lmmunoglobin level
(mg/lOO ml)
IgG 900-1,800 680
IgA 156-294 82
IgM 67-145 48
“Cellular” Immunity
Skin tests (% positive)
(13-15)
Purified protein
derivative 24-70 Negative
Mumps antigen 90 Negative Candida 50-90 Negative
SK/SD 66 Negative
Inflammatory Response
DNCB-sensitizing dose Acute inflammation No reaction
February 1973 The American Journal of Medicine Volume 54 225
HERPES SIMPLEX ENCEPHALITIS-PRICE ET AL
TABLE II Viral Serologic Studies .___
Virus Method Serum Titer
Herpesvirus hominis type 1 Herpesvirus hominis type 1
Herpesvirus hominis type 1
Herpesvirus hominis type 2
Rubeola
Indirect hemagglutination
Complement fixation Complement fixation
Indirect hemagglutination
Hemagglutination inhibition
Rubeola Complement fixation
Varicella-zoster Complement fixation
Cytomegalovirus Complement fixation
tured monolayers with known HVH antiserums
showed some intranuclear but predominantly
intracytoplasmic fluorescence. The fluorescent
reaction was strongly positive with type 1 antise-
rum, weakly positive with type 2 antiserum and negative with HVH antibody-free serum, suggest-
ing that the isolate was HVH type 1. Cell-free tis-
sue culture fluids derived from the brain cultures
were inoculated into monolayers of human diploid
cell line (WI-38) and primary rabbit kidney. The
same characteristic cytopathic effect appeared after 48 hours of incubation. Indirect immunofluo-
rescent tests with these cultures revealed specific
immunofluorescence with HVH type 1 antiserum.
COMMENTS
This patient’s illness is interesting from several
aspects: (1) He had an exceedingly unusual clini-
cal course with unusual pathologic findings in the
central nervous system. (2) He failed to respond
to therapy with an antiviral agent which has been reported to successfully control some cases of
herpes simplex encephalitis. (3) The differences between the patient’s clinical-pathologic findings
and those in other patients with normal immune mechanisms raise the question of the relative
contribution of the virus and host to the develop-
ment of the disease process. (4) The method of virus isolation and histopathologic findings sug-
gested a different virus-cell relationship than that usually seen in herpes hominis encephalitis. Clinical and Pathologic Findings. The clinical fea-
tures of herpes simplex encephalitis have been
well defined [2-41. The encephalitis is usually a fulminant illness heralded by a few days of prod-
romal symptoms such as headache, fever, nau- sea and vomiting. When central nervous system signs develop, they are usually acute and severe,
with changes in behavior, alterations of con- sciousness and seizures predominating. The focal findings often suggest a temporal lobe lesion, and brain scan and contrast studies may support this diagnosis [2,4]. The electroencephalogram with a
1:1024
1:16
1:16 1:8
1:8
1:7
1:16 1:8
Cerebrospinal
Fluid Titer
1:8
. .
<1:8
0
0
0 . . . . . .
Date _..._~__.
g/17/71
g/4/71
g/29/71
g/17/71
g/17/71
g/17/71 g/17/71
g/4/71 _
diffuse slow wave background upon which is superimposed periodic complexes may be focal or
generalized and this electroencephalographic pat- tern is believed by some investigators to be spe-
cific for herpes simplex encephalitis [7]. Cerebro- spinal fluid examination usually reveals a pleocy-
tosis with some red blood cells in addition, and, if
the illness lasts long enough, a rising complement fixation antibody titer to herpes simplex in the
serum and spinal fluid can be detected. The diag-
nosis is established by brain biopsy.
Our patient’s symptoms differed in almost all respects from the typical clinical history. There
was no prodromal illness and his neurologic signs
were those of a slowly progressive disease begin- ning first in the gray matter of the right frontopari-
etal region and later involving several other areas
in both hemispheres and in the brainstem. The
spinal fluid was uninformative and contrast studies
demonstrated no mass effect. A brain scan
showed no disruption of the blood-brain barrier.
The electroencephalogram, which was abnormal
and worsened as his clinical course progressed, was not the typical electroencephalogram of a pa-
tient with herpes simplex encephalitis. This unusu-
al ciinical picture led us away from that diagnosis,
and it was not until the very high titers against
HVH type 1 as determined by indirect hemaggluti-
nation, but not by complement fixation, were de- tected that the diagnosis became sufficiently plau-
sible to begin treatment. The pathologic picture was also atypical. In
most cases [2,3], there is lymphocytic infiltration
of the meninges, perivascular aggregation of lym- phocytes and macrophages in the cortex and ad- jacent white matter, and proliferation of glial nod-
ules. Pathologic changes are often confined to or most marked in the medial temporal and inferior frontal regions of the brain, producing an intense
necrotic tissue reaction [2]. The clinical correlate of these changes is the shedding of both red and white cells into the spinal fluid, the breakdown of the blood-brain barrier resulting in the positive
226 February 1973 The American Journal of Medicine Volume 54
brain scan in many patients, and the evidence of a temporal mass lesion on arteriogram or pneu-
moencephalogram.
Our patient had none of these findings and, al- though his white cell count was low at the time of death, failure of a pleocytosis to develop in the
spinal fluid when his counts were normal early in
his course suggests that none of these changes
had ever been present.
A further characteristic, although not diagnostic [3], finding in herpes simplex encephalitis is the
presence of Cowdry type A inclusion bodies which
can be identified in neurons, astrocytes and oligo- dendroglia. Electronmicroscopy has confirmed
that these represent an alteration of the nucleo-
plasm induced by active viral infection, probably
related to replication [6,8]. In our patient, only this finding was present. Cowdry type A inclusion
bodies were seen in abundance throughout the brain accompanied by neuronal and glial degen-
eration and reactive astrocytosis. Special predi-
lection for the inferior frontal and temporal lobes
was not detected. The pathologic changes, in-
deed, were so different that without specific cul-
tural evidence of herpes simplex virus, one would
be loathe to believe that this organism was pres-
ent in this patient’s brain. However, the agent was
isolated and identified in tissue culture derived
from the brain biopsy specimen. Response to Therapy. Sporadic favorable thera- peutic results have been reported first with idoxuri-
dine [9,10] and more recently with cytosine arab-
inoside [11,12]. In our patient, the drug was ad-
ministered via the intraventricular route because
the drug crosses the blood-brain barrier poorly
[13] and there was little evidence of the usual dis-
ruption of this barrier by the disease. Cytosine ar-
abinoside has been used by this route for the
treatment of various disorders, particularly menin-
geal leukemia [14], but also once previously for
herpes simplex encephalitis [12]. Despite the in-
jection of several doses of the drug into the ven-
tricular system, there was no discernible change
in the patient’s course, it being inexorably pro-
gressive until death.
HERPES SIMPLEX ENCEPHALITIS-PRICE ET AL.
Pathogenesis. Our patient differed in only one
important respect from most patients with herpes
simplex encephalitis in that he suffered a severe
depression of normal immunologic defense mech-
anisms (Table I). Comparison of the course of the disease in our patient with the usual course
suggests that acute necrotizing encephalitis is
produced by two processes: (1) the direct cytotoxicity of the virus, and (2) immune mecha-
nisms which then effect further tissue destruction.
In our patient, only the first of these two was op-
erant and the virus destroyed neurons and glia, producing symptoms of local cellular dysfunction
with widespread involvement by the time of his
death. In tissue culture, the virus has been ob-
served to be cytolytic [15], and it is presumed
that the widespread injury and death of nervous
tissue seen in this case is most easily attributable
to such a direct toxic effect of the virus on infect- ed cells. The spread of the virus may have oc-
curred by cell to cell transmission, via extracellu-
lar fluid, over spinal fluid pathways or hematogen-
ously. A hematogenous dissemination is suggest-
ed by the inclusion bodies found in the liver. The
inexorable spread of the virus was potentiated by
poor defense mechanisms rendered unable to
check propagation of the virus. Studies in animals
have demonstrated similar increased dissemina-
tion of herpes simplex virus by immunosuppres-
sion [16]. This may also explain the difference be- tween the diffuse central nervous system disease in our patient and the more focal changes ob-
served in the usual patient with herpes simplex en-
cephalitis. By contrast, many of the clinical and pathologic
features seen more commonly, but absent in our
patient, probably result from host immune re-
sponses rather than from a direct effect of the
virus. The usual findings, missing in our case, in-
clude perivascular mononuclear infiltrates and
glial nodules. Absent also were the large areas of
hemorrhagic necrosis with intense destruction of
brain tissue. These reactions are probably in part the result of an immune phenomenon evoked in
the host by the virus.
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6. Chou SM. Cherry JD: Ultrastructure of Cowdry type A inclusions. I. In human herpes simplex encephalitis. Neurology 17: 575, 1967.
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10. Nolan DC, Carruthers MM, Lerner AM: Herpesvirus hominis encephalitis in Michigan. Report of 13 cases, including 6 treated with Idoxuridine. New Eng J Med 282: 10, 1970.
11. Farris WA, Blaw ME: Cytarabine treatment of herpes simplex encephalitis. Arch Neurol 27: 99, 1972.
12. Hryniuk W, Foerster J, Shojania M, Chow A: Cytarabine for herpesvirus infections. JAMA 219: 715, 1972.
13. Dixon RL, Adamson RH: Antitumor activity and pharma- cologic disposition of cytosine arabinoside (NCS- 63878). Cancer Chemother Rep 48: 11, 1965.
14. Wang JJ, Pratt CB: lntrathecal arabinosyl cytosine in meningeal leukemia. Cancer 25: 531, 1970.
15. Dudgeon JA: Herpes simplex, Modern Trends in Medi- cal Virology, vol 2 (Heath RB, Waterson AP, eds), New York, Appleton-Century-Crofts, 1970, p 78.
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228 February 1973 The American Journal of Medicine Volume 54